Heart failure in aging women differs from that in aging men, with more frequent diastolic dysfunction due to increased cardiac stiffness, for which there is no specific treatment. Premenopausal women appear to be protected from diastolic dysfunction, with a rapid increase in its incidence after menopause. Clinical evidence strongly suggests that the interaction between estrogen loss and activation of the cardiac renin-angiotensin-aldosterone system (RAAS) contributes to the development of hypertension and left ventricular (LV) hypertrophy in postmenopausal women, two risk factors for diastolic dysfunction. We have found that early estrogen depletion in the female mRen2 Lewis rat, a novel congenic strain, triggers the development of diastolic dysfunction, manifested by a pseudonormal Doppler pattern and increase in E/e' (reflective of high filling pressures); this is associated with increased cardiac collagen and serum aldosterone. These data lead to the overall hypothesis that loss of estrogen regulates two key enzymatic pathways within the cardiac RAAS to enhance ACE and suppress ACE2. The imbalance in these two enzymes ultimately results in sustained expression of angiotensin II and aldosterone, and a corresponding reduction in angiotensin-(1-7), promoting LV remodeling and diastolic stiffness. Using a reverse translational approach in ovariectomized versus estrogen-intact mRen2 rats, we will determine whether: 1) a shift from the antifibrotic to profibrotic limb of the cardiac RAAS contributes to LV remodeling and diastolic dysfunction following estrogen loss; 2) estrogen replacement attenuates diastolic dysfunction by shifting the balance of the RAAS to ACE2 and angiotensin-(1-7); and 3) ACE2 inhibition attenuates the cardioprotective benefits of estrogen. The results from this study will be important because diastolic dysfunction is highly prevalent among postmenopausal women, yet the mechanisms and therefore optimal therapy are not well defined. PUBLIC HEALTH RELEVANCE: Diastolic dysfunction contributes significantly to age-related heart failure, a major problem among elderly women. The overall goal of this proposal is to delineate the role of estrogen in the modulation of the cardiac renin-angiotensin-aldosterone system as it leads to cardiac remodeling and diastolic dysfunction using an established rodent model of hypertension and surgical menopause. Our results will help clarify optimal treatment of diastolic heart disease in postmenopausal women.